Methods for embolizing blood vessels

ABSTRACT

Disclosed are methods useful for treating vascular lesions wherein a non-particulate agent such as a metal coil is introduced into a vascular site (e.g., an aneurysm cavity) in conjunction with an embolizing composition comprising a biocompatible polymer and a biocompatible solvent. 
     The biocompatible solvent is miscible or soluble in blood and also solubilizes the polymer during delivery. The biocompatible polymer is selected to be soluble in the biocompatible solvent but insoluble in blood. Upon contact with the blood, the biocompatible solvent dissipates from the embolic composition whereupon the biocompatible polymer precipitates. Precipitation of the polymer in the presence of the non-particular agent permits the agent to act as a structural lattice for the growing polymer precipitate. 
     In another embodiment, the biocompatible polymer composition can be replaced with a biocompatible prepolymer composition containing a biocompatible prepolymer.

This application is a continuation of application Ser. No. 09/438,929,filed Nov. 12, 1999 now U.S. Pat. No. 6,281,263, which is a continuationof application Ser. No. 08/868,931 filed on Jun. 4, 1997, now U.S. Pat.No. 6,017,977 which in turn is a divisional of application Ser. No.08/594,574 filed Jan. 31, 1996, now U.S. Pat. No. 5,702,361.

BACKGROUND OF THE INVENTION

Field of the Invention

This invention is directed to methods for embolizing blood vessels whichmethods are particularly suited for treating vascular lesions. In thesemethods, a non-particulate agent such as a metal coil is introduced intoa vascular site (e.g., an aneurysm cavity) in conjunction with anembolizing composition comprising a biocompatible polymer and abiocompatible solvent.

The biocompatible solvent is miscible or soluble in blood and alsosolubilizes the polymer during delivery. The biocompatible polymer isselected to be soluble in the biocompatible solvent dissipates from theembolic composition whereupon the biocompatible polymer precipitates.Precipitation of the polymer in the presence of the non-particulateagent permits the agent to act as a structural lattice for the growingpolymer precipitate.

REFERENCES

The following publications are cited in this application as superscriptnumbers:

¹ Castaneda-Zuniga et al., Interventional Radiology, in VascularEmbolotherapy, Part 1, 1:9-32, Williams & Wilkins, Publishers (1992)

² Hopkins, et al., “Endovascular Treatment of Aneurysms and CerebralVasospasms”, in “Current Management of Cerebral Aneurysms”, Am. Assoc.Neuro. Surgeons, A. Awad, Editor, Chapter II, pp. 219-242 (1993).

³ Pruvo, et al., “Endovascular Treatment of 16 Intercranial Aneurysmswith Microcoils”, Neuroradiology, 33(suppl):S144 (Abstract) (1991).

⁴ Mandai, et al., “Direct Thrombosis of Aneurysms with Cellulose AcetatePolymer”, J. Neurosurg., 77:497-500 (1992)

⁵ Kinugasa, et al., “Direct Thrombosis of Aneurysms with CelluloseAcetate Polymer”, J. Neurosurg., 77:501-507 (1992)

⁶ Casarett and Doull's Toxicology, Amdur et al., Editors, PergamonPress, New York, pp. 661-664 (1975)

⁷ Greff, et al., U.S. Pat. No. 5,667,767, filed as U.S. patentapplication Ser. No. 08/507,863 for “Novel Compositions for Use inEmbolizing Blood Vessels”, filed Jul. 27, 1995.

⁸ Greff, et al., U.S. Pat. No. 5,580,568, filed as U.S. patentapplication Ser. No. 08/508,248 for “Cellulose Diacetate Compositionsfor Use in Embolizing Blood Vessels”, filed Jul. 27, 1995.

⁹ Kinugasa, et al., “Early Treatment of Subarachnoid Hemorrhage AfterPreventing Rerupture of an Aneurysm”, J. Neurosurg., 83:34-41 (1995)

¹⁰ Kinugasa, et al., “Prophylactic Thrombosis to Prevent New Bleedingand to Delay Aneurysm Surgery”, Neurosurg., 36:661 (1995)

¹¹ Taki, et al., “Selection and Combination of Various EndovascularTechniques in the Treatment of Giant Aneurysms”, J. Neurosurg., 77:37-42(1992)

¹² German, et al., New England Journal of Medicine, 250:104-106 (1954)

¹³ Rabinowitz, et al., U.S. Pat. No. 3,527,224, for “Method ofSurgically Bonding Tissues Together”, issued Sep. 8, 1970

¹⁴ Hawkins, et al., U.S. Pat. No. 3,591,676, for “Surgical AdhesiveCompositions”, issued Jul. 6, 1971

All of the above references are herein incorporated by reference intheir entirety to the same extent as if each individual reference wasspecifically and individually indicated to be incorporated herein byreference in its entirety.

STATE OF THE ART

Embolization of blood vessels is conducted for a variety of purposesincluding the treatment of tumors, the treatment of lesions such asaneurysms, arteriovenous malformations (AVM), arteriovenous fistula(AVF), uncontrolled bleeding and the like.

Embolization of blood vessels is preferably accomplished via cathetertechniques which permit the selective placement of the catheter at thevascular site to be embolized. In this regard, recent advancements incatheter technology as well as in angiography now permit neuroendovascular intervention including the treatment of otherwiseinoperable lesions. Specifically, development of microcatheters andguide wires capable of providing access to vessels as small as 1 mm indiameter allows for the endovascular treatment of many lesions.

Endovascular treatment regimens include the use of non-particulateagents such as metal coils which are designed to induce thrombosis afterdelivery to the vascular site.¹ Ideally, after placement of themicrocoils at the vascular site, thrombosis results in the formation ofa clot about the coil thereby sealing the vascular site.

Complications in this procedure have, however, been reported includingthe fact that thrombosis about the metal coil is not uniform in natureand fragmentation of the resulting clot can occur. This former aspectcan lead to incomplete sealing of, for example, vascular lesions,whereas the latter aspect can lead to migration of the blood clots inthe patient's circulation.

Additionally, while platinum has been the metal of choice for use inmetal coils, the thrombogenic potential of platinum coils is variable²and can result in incomplete sealing of the blood vessel (e.g.,aneurysm). Likewise, when employed in treating aneurysms, coils areprone to migration in and/or from the aneurysm cavity after placement².Coil migration away from the aneurysm cavity in such cases has beenreported to result in regressive complete motor paralysis in treatmentpatients.³ Likewise, migration within the aneurysm cavity prior tothrombosis can liberate calcified emboli from within the aneurysm cavityand cause intimal tears and vessel wall dissections.²

Still further, in the embolization of blood vessels, the choice of coilsize is critical because the use of microcoils which are too small canresult in coil migration within the patient's circulation and the use ofcoils which are too large for the blood vessel to be embolized canresult in coil elongation which is recognized to be less efficient forblood vessel embolization.¹

While efforts have been made to improve the thrombogenic properties ofplatinum coils by the incorporation of Dacron® threads onto the coils,coil migration remains a serious concern primarily due to potentialsevere adverse affects arising from such migration. Moreover, sincethrombosis around the coils is essential for successful treatment of theaneurysm, care must be taken to minimize any breakage of clot fragmentsfrom the formed clot and incorporation of these fragments into thepatient's circulation.

Still further, in treatment of lesions, it is common to employ multiplecoils to effect thrombosis. However, the positioning and placement ofmultiple coils is technically challenging and often results in undesiredcoil migration, misplacement and/or altered shape of the coil pack.

In view of the above, there is an ongoing need to enhance the efficacyof blood vessel embolization using non-particulate agents such as metalcoils.

This invention is directed to the discovery that the efficacy of bloodvessel embolization via catheter delivery of microcoils and othernon-particulate agents to the blood vessel site to be embolized can beenhanced by further delivering a polymer composition as described belowto this site. The deposited coils or other non-particulate agents act asa lattice about which a polymer precipitate grows thereby embolizing theblood vessel.

While the use of polymer compositions to embolize blood vessels hasheretofore been disclosed including compositions wherein a preformedpolymer precipitates in situ from a carrier solution at the vascularsite to be embolized,^(4,5) such compositions invariably have beenemployed by themselves in the absence of non-particulate agents such asmetal coils. For effective treatment, such polymer compositions mustform a precipitate in the blood vessel having sufficient structuralintegrity to inhibit fragmentation of the precipitate and theprecipitate must be anchored at the site of placement. While certainpolymer compositions form precipitates having the requisite structuralintegrity^(7,8), other polymer compositions do not. In either case,anchoring of these precipitates to the vascular site remains a seriousproblem particularly in lesions having high blood flow and/or diffusenecks. In such cases, precipitate anchoring to the vascular site is notan intrinsic function of the shape of the lesion to be treated andmigration of the precipitate away from the intended vascular site canoccur.

In view of the above, there is an ongoing need for enhancing theefficacy of polymer compositions used for embolizing vascular sites.

SUMMARY OF THE INVENTION

This invention is directed to the discovery that unexpected andsurprising results are achieved when blood vessels are embolized with acombination of a non-particulate agent and a polymer composition in themanner described herein. In particulate, deficiencies associated witheach of these embolizing procedures when used separately are eitherreduced of eliminated by using these procedures in combination. Suchdeficiencies addressed by this invention include, for example, (a)problems associated with variable thrombosis that the non-particulateagent at the vascular site, (b) problems associated with non-particulateagent migration after delivery to the vascular site, (c) problemsassociated with polymer precipitate fragmentation after precipitateformation at the vascular site, and (d) problems associated with polymerprecipitate anchoring at the vascular site.

Accordingly, in one of its method aspects, this invention is directed toa method for embolizing a vascular site in a patient's blood vesselwhich method comprises

(a) introducing, via a catheter, at the vascular site to be embolized anon-particulate agent or a plurality of said agents; and

(b) delivering, via a catheter, to said vascular site a polymercomposition comprising a biocompatible polymer, a biocompatible solventand a contrast agent

wherein said delivery is conducted under conditions wherein a polymerprecipitate forms in situ at said vascular site thereby embolizing theblood vessel and further wherein said non-particulate agent isencapsulating within said precipitate.

In the polymer composition, the biocompatible solvent is preferablydimethyl sulfoxide (DMSO) and the biocompatible polymer is preferably anethylene vinyl alcohol copolymer or a cellulose acetate polymer.

In another embodiment, the biocompatible polymer composition can bereplaced with a biocompatible prepolymer composition containing abiocompatible prepolymer. In this embodiment, this invention is directedto a method for embolizing a vascular site in a patient's blood vesselwhich method comprises

(a) introducing, via a catheter, at the vascular site to be embolized anon-particulate agent or a plurality, of said agents; and

(b) delivering, via a catheter, to said vasculate site a prepolymercomposition comprising a biocompatible prepolymer and a contrast agent

wherein said delivery is conducted under conditions wherein saidprepolymer polymerized in situ at said vascular site thereby embolizingthe blood vessel and further wherein said non-particulate agent isencapsulated within said polymer.

In one optional embodiment, the prepolymer composition further comprisesa biocompatible solvent which is preferably selected from the groupconsisting of dimethylsulfoxide, ethanol, and acetone.

In one of its kit aspects, this invention is directed to a kit of partscomprising:

(a) a polymer composition comprising a biocompatible polymer, abiocompatible solvent and a contrast agent; and

(b) a non-particulate agent or plurality of such agents.

In another of its kit aspects, this invention is directed to a kit ofparts comprising:

(a) a prepolymer composition comprising a biocompatible prepolymer and acontrast agent; and

(b) a non-particulate agent or plurality of such agents.

Preferably, the kit further comprises a catheter capable of deliveringsaid polymer composition.

In one embodiment, the catheter capable of delivering said polymercomposition is the same as the catheter capable of delivering saidnon-particulate agent. In another embodiment, the catheter capable ofdelivering said polymer composition is different from the cathetercapable of delivering said non-particulate agent. In this latterembodiment, the kit further comprises a catheter capable of deliveringsaid non-particulate agent.

In another embodiment, the kit further comprises a microballoon catheterto arrest blood flow.

DETAILED DESCRIPTION OF THE INVENTION

This invention is directed to methods for embolizing vascular siteswhich methods incorporate both a non-particulate agent and a polymer orprepolymer composition at the vascular site to be embolized.

However, prior to discussing this invention is further detail, thefollowing terms will first be defined:

The term “embolizing” refers to a process wherein a material is injectedinto a blood vessel which, in the case of for example aneurysms, fillsor plugs the aneurysm sac and/or encourages clot formation so that bloodflow into the aneurysm ceases, and in the case of AVM's and AVF's formsa plug or clot to control/reroute blood flow to permit proper tissueperfusion. Embolization of the blood vessel is, therefore, important inpreventing/controlling bleeding due to lesions (e.g., organ bleeding,gastrointestinal bleeding, vascular bleeding as well as bleedingassociated with an aneurysm). In addition, embolization can be used toablate diseased tissue (e.g., tumors, etc.) by cutting off its bloodsupply.

The term “non-particulate agent” refers to biocompatible macroscopicsolid materials having a discrete physical shape or structure which,when placed in a blood vessel, result in embolization of the bloodvessel. The non-particulate agents are macroscopic (i.e., about 1 mm orlarge in size) which is contrasted with particulates which aremicroscopic (i.e., less than 1 mm in size). Examples of suchnon-particulate agents include, coils (including metallic coils, coilswith barbs, etc.), silk streamers, plastic brushes, detachable balloons(e.g., silicon or latex balloons), foam (e.g., polyvinyl alcohol foam),nylon mesh and the like. Such non-particulate agents are generallycommercially available. For example, platinum coils are available fromTarget Therapeutics, San Jose, Calif., U.S.A.

The specific non-particulate agent employed is not critical andpreferred agents include metallic coils, metallic coils with barbs,metallic coils with fibers (e.g., Dacron® wool fibers) and/or streamers,etc. More preferably, platinum coils are employed.

The term “biocompatible polymer” refers to polymers which, in theamounts employed, are non-toxic, chemically inert, and substantiallynon-immunogenic when used internally in the patient and which aresubstantially insoluble in blood. Suitable biocompatible polymersinclude, by way of example, cellulose acetates^(5,9-10) (includingcellulose diacetate⁸), ethylene vinyl alcohol copolymers^(7,11),hydrogels (e.g., acrylics), polyacrylonitrile and the like. Preferably,the biocompatible polymer is also non-inflammatory when employed insitu.

The particulate biocompatible polymer employed is not critical and isselected relative to the viscosity of the resulting polymer solution,the solubility of the biocompatible polymer in the biocompatiblesolvent, the compatibility of the polymer composition with thenon-particulate agent and the like. Such factors are well within theskill of the art.

Preferred biocompatible polymers include cellulose diacetate andethylene vinyl alcohol copolymer. Cellulose diacetate polymers areeither commercially available or can be prepared by art recognizedprocedures. In a preferred embodiment, the number average molecularweight, as determined by gel permeation chromatography, of the cellulosediacetate composition is from about 25,000 to about 100,000 morepreferably from about 50,000 to about 75,000 and still more preferablyfrom about 58,000 to 64,000. The weight average molecular weight of thecellulose diacetate composition, as determined by gel permeationchromatography, is preferably from about 50,000 to 200,000 and morepreferably from about 100,000 to about 180,000. As is apparent to oneskilled in the art, with all other factors being equal, cellulosediacetate polymers having a lower molecular weight will impart a lowerviscosity to the composition as compared to higher molecular weightpolymers. Accordingly, adjustment of the viscosity of the compositioncan be readily achieved by mere adjustment of the molecular weight ofthe polymer composition.

Ethylene vinyl alcohol copolymers comprise residues of both ethylene andvinyl alcohol monomers. Small amounts (e.g., less than 5 mole percent)of additional monomers can be included in the polymer structure orgrafted thereon provided such additional monomers do not alter theembolizing properties of the composition. Such additional monomersinclude, by way of example only, maleic anhydride, styrene, propylene,acrylic acid, vinyl acetate and the like.

Ethylene vinyl alcohol copolymers are either commercially available orcan be prepared by art recognized procedures. Preferably, the ethylenevinyl alcohol copolymer composition is selected such that a solution of6 weight percent of the ethylene vinyl alcohol copolymer, 35 weightpercent of a tantalum contrast agent in DMSO has a viscosity equal to orless than 60 centipoise at 20° C. As is apparent to one skilled in theart, with all other factors being equal, copolymers having a lowermolecular weight will impart a lower viscosity to the composition ascompared to higher molecular weight copolymers. Accordingly, adjustmentof the viscosity of the composition as necessary for catheter deliverycan be readily achieved by mere adjustment of the molecular weight ofthe copolymer composition.

As is also apparent, the ratio of ethylene to vinyl alcohol in thecopolymer affects the overall hydrophobicity/hydrophilicity of thecomposition which, in turn, affects the relative watersolubility/insolubility of the composition as well as the rate ofprecipitation of the copolymer in an aqueous solution (e.g., blood). Ina particularly preferred embodiment, the copolymers employed hereincomprise a mole percent of ethylene of from about 25 to about 60 and amole percent of vinyl alcohol of from about 40 to about 75. Thesecompositions provide for requisite precipitate rates suitable for use inembolizing blood vessels.

The term “contrast agent” refers to a radiopaque material capable ofbeing monitored during injection into a mammalian subject by, forexample, radiography. The contrast agent can be either water soluble orwater insoluble. Examples of water soluble contrast agents includemetrizamide, iopamidol, iothalamate sodium, iodomide sodium, andmeglumine. Examples of water insoluble contrast agents include tantalum,tantalum oxide and barium sulfate, each of which is commerciallyavailable in the proper form for in vivo use including a particle sizeof about 10 μm or less. Other water insoluble contrast agents includegold, tungsten and platinum.

Preferably, the contrast agent is water insoluble (i.e., has a watersolubility of less than 0.01 mg/lml at 20° C.).

The term “biocompatible solvent” refers to an organic material liquid atleast at body temperature of the mammal in which the biocompatiblepolymer is soluble and, in the amounts used, is substantially non-toxic.Suitable biocompatible solvents include, by way of example,dimethylsulfoxide, analogues/homologues of dimethylsulfoxide, ethanol,acetone, and the like. Aqueous mixtures with the biocompatible solventcan also be employed provided that the amount of water employed issufficiently small that the dissolved polymer precipitates upon contactwith the blood. Preferably, the biocompatible solvent isdimethylsulfoxide.

The term “encapsulation” as used relative to the contrast agent and/ornon-particulate agent being encapsulated in the polymer precipitate isnot meant to infer any physical entrapment of the contrast agent withinthe precipitate much as a capsule encapsulates a medicament. Rather,this term is used to mean that an integral coherent precipitate formswhich does not separate into individual components.

The term “biocompatible prepolymer” refers to materials which polymerizein situ to form a polymer and which, in the amounts employed, arenon-toxic, chemically inert, and substantially non-immunogenic when usedinternally in the patient and which are substantially insoluble inblood. Suitable biocompatible prepolymers include, by way of example,cyanoacrylates^(1,13,14), hydroxyethyl methyacrylate, siliconprepolymers, and the like. The prepolymer can either be a monomer or areactive oligomer¹³. Preferably, the biocompatible prepolymer is alsonon-inflammatory when employed in situ.

Compositions

The polymer or prepolymer compositions employed in the methods of thisinvention are prepared by conventional methods whereby each of thecomponents is added and the resulting composition mixed together untilthe overall composition is substantially homogeneous.

For example, polymer compositions can be prepared by adding sufficientamounts of the biocompatible polymer to the biocompatible solvent toachieve the effective concentration for the polymer composition.Preferably, the polymer composition will comprise from about 2.5 toabout 8.0 weight percent of the biocompatible polymer composition basedon the total weight of the polymer composition and more preferably fromabout 4 to about 5.2 weight percent. If necessary, gentle heating andstirring can be used to effect dissolution of the biocompatible polymerinto the biocompatible solvent, e.g., 12 hours at 50° C.

Sufficient amounts of the contrast agent are then added to the solutionto achieve the effective concentration for the complete polymercomposition. Preferably, the polymer composition will comprise fromabout 10 to about 40 weight percent of the contrast agent and morepreferably from about 20 to about 40 weight percent and even morepreferably 35 weight percent. When the contrast agent is not soluble inthe biocompatible solvent, stirring is employed to effect homogeneity ofthe resulting suspension. In order to enhance formation of thesuspension, the particle size of the contrast agent is preferablymaintained at about 10 μm or less and more preferably at from about 1 toabout 5 μm (e.g., an average size of about 2 μm).

The particulate order of addition of components to the biocompatiblesolvent is not critical and stirring of the resulting suspension isconducted as necessary to achieve homogeneity of the composition.Preferably, mixing/stirring of the composition is conducted under ananhydrous atmosphere at ambient pressure. The resulting composition isheat sterilized and then stored preferably in sealed amber bottles orvials until needed.

Prepolymer compositions can be prepared by adding sufficient amounts ofthe contrast agent to the solution to achieve the effectiveconcentration for the complete polymer composition. Preferably, theprepolymer composition will comprise from about 10 to about 40 weightpercent of the contrast agent and more preferably from about 20 to about40 weight percent and even more preferably 35 weight percent. When thecontrast agent is not soluble in the biocompatible prepolymercomposition, stirring is employed to effect homogeneity of the resultingsuspension. In order to enhance formation of the suspension, theparticle size of the contrast agent is preferably maintained at about 10μm or less and more preferably at from about 1 to about 5 μm (e.g., anaverage size of about 2 μm).

When the prepolymer is liquid (as in the case of polyurethanes), the useof a biocompatible solvent is not absolutely necessary but may bepreferred to provide for an appropriate viscosity, etc. in the emboliccomposition. Preferably, when employed, the biocompatible solvent willcomprise from about 50 to about 90 weight percent of the biocompatibleprepolymer composition based on the total weight of the prepolymercomposition and more preferably from about 60 to about 80 weightpercent.

In a particularly preferred embodiment, the prepolymer is cyanoacrylatewhich is preferably employed in the absence of a biocompatible solvent.When so employed, the cyanoacrylate adhesive is selected to have aviscosity of from about 5 to about 20 centipoise at 20° C.

The particular order of addition of components is not critical andstirring of the resulting suspension is conducted as necessary toachieve homogeneity of the composition. Preferably, mixing/stirring ofthe composition is conducted under an anhydrous atmosphere at ambientpressure. The resulting composition is sterilized and then storedpreferably in sealed amber bottles or vials until needed.

Methods

The composition described above are then employed in methods forembolizing mammalian blood vessels. In these methods, thenon-particulate agent (e.g., platinum coils) is first introduced to thevascular site to be embolized via conventional catheter technology. See,for example, Hopkins et al.² for a discussion of conventional cathetertechniques for introduction of such agents into the vascular site.

After introduction of the non-particulate agent to the vascular site, asufficient amount of the polymer composition is introduced byconventional means (e.g., catheter delivery under fluoroscopy). Upondischarge of the polymer composition from the catheter into the vascularsite, the biocompatible solvent dissipates into the blood resulting inprecipitation of the biocompatible polymer. The precipitate forms aroundthe non-particulate agent which acts as a lattice for precipitate growthand eventual blood vessel embolization. In turn, the non-particulateagent anchors the growing precipitate to the vascular site and isselected relative to its ability to remain at the vascular site.

The particulate amount of polymer composition employed in dictated bythe total volume of the vasculature to be embolized, the concentrationof polymer in the composition, the rate of precipitate (solidsformation) of the polymer, the size and number of non-particulate agentemployed, etc. Such factors are well within the skill of the art. Forexample, the rate of precipitation can be controlled by changing theoverall hydrophobicity/hydrophilicity of the polymer with fasterprecipitation rates being achieved by a more hydrophobic polymercomposition.

The particulate combination of non-particulate agent and polymercomposition employed is governed by the compatibility of these materialswith each other. Each component is deemed compatible if it isessentially inert in the presence of the other components. For example,when dimethyl sulfoxide is employed as the biocompatible solvent in thepolymer composition, the non-particulate agent is selected to becompatible with this solvent. Accordingly, plastic, wool and wood coilswould typically not be employed in combination with such a polymercomposition insofar as such coils may degrade in the presence ofdimethyl sulfoxide. Contrarily, platinum coils are essentially inert inthe presence of dimethyl sulfoxide and, accordingly, such a combinationwould be compatible.

One particularly preferred method for delivering the non-particulateagent and the polymer composition to the selected vascular site is via asmall diameter medical catheter. The particulate catheter employed isnot critical provided that polymeric catheter components are compatiblewith the polymeric composition (i.e., the catheter components will notreadily degrade in the polymer composition and none of the components ofthe polymer compositions will readily degrade in the presence of thecatheter components). In this regard, it is preferred to usepolyethylene in the catheter components because of its inertness in thepresence of the polymeric composition described herein. Other materialscompatible with the embolizing compositions can be readily determined bythe skilled artisan and include, for example, other polyolefins,fluoropolymers (e.g., Teflon™), silicone, etc.

When delivered by catheter, the injection rate of the polymercomposition dictates, in part, the form of the precipitate at thevascular site. Specifically, low injection rates of approximately 0.05to 0.3 cc/minute will provide for a precipitate in the form of a kernelor nodule which is particularly beneficial for site specificembolization (e.g., aneurysms) because the precipitate forms primarilyat the point of injection. Contrarily, high injection rates of about 0.1to 0.5 or more cc/several seconds (e.g., up to 10 seconds) will providefor a filament like mass projecting downstream from the catheter tipwhich is particularly beneficial for providing the embolizing agent deepinto the vascular tree. Such procedures are suitable for embolizingtumor masses and organs.

When introduced into the vascular site, the non-particulate agent maybecome fixed against the vascular wall thereby anchoring the embolicsite. Addition of the polymer composition to this site results in rapiddiffusion of the biocompatible solvent into the blood and asolid-precipitate forms which precipitate is the biocompatiblepolymer/contrast agent with the non-particulate agent encapsulatedtherein. Without being limited to any theory, it is believed thatinitially, a soft gel to spongy solid precipitate forms upon contractwith the blood and non-particulate agent which precipitate is open andfibrous in structure and forms around the non-particulate agent. Thisprecipitate then restricts blood flow, entrapping red cells therebycausing clot embolization of the blood vessel.

Without being limited to any theory, the methods of this inventionaddress the prior art problems recited above because problems associatedwith variable thrombosis about the non-particulate agent at the vascularsite are reduced because this agent is encapsulated in the polymerprecipitate are further because this agent is not the only thrombicagent employed to effect embolization but rather is employed inconjunction with the polymer precipitate. Also, encapsulation of thenon-particulate agent in the polymer composition minimizes migration ofthese agents. Additionally, since the non-particulate agent acts as astructural lattice, the structural integrity of the precipitate isenhanced thereby minimizing fragmentation. Lastly, because thenon-particulate agent acts as an appropriate anchor, the precipitate isheld in position more effectively than if only the polymer compositionwas employed to embolize the blood vessel.

The methods described herein can also employ a biocompatible prepolymersuch as cyanoacrylate in place of or in conjunction with the polymercomposition described above. When the prepolymer is liquid (as in thecase of cyanoacrylates), the use of a biocompatible solvent is notabsolutely necessary but may be preferred to provide for an appropriateviscosity, etc. in the embolic composition. Upon injection into thevascular site, the prepolymer will polymerize in situ upon contact withthe blood and form a solid polymer around the non-particulate agentthereby encapsulating this agent in the polymer and embolizing the bloodvessel.

For polymer compositions, the methods of this invention are convenientlypracticed by use of a kit of parts comprising:

(a) a polymer composition comprising a biocompatible polymer, abiocompatible solvent and a contrast agent; and

(b) a non-particulate agent or plurality of such agents.

For prepolymer compositions, the methods of this invention areconveniently practiced by use of a kit of parts comprising:

(a) a prepolymer composition comprising a biocompatible prepolymer and acontrast agent; and

(b) a non-particulate agent or plurality of such agents.

Preferably, in either case, the kit further comprises a catheter capableof delivering said polymer or prepolymer composition.

In one embodiment, the catheter capable of delivering said polymer orprepolymer composition is the same as the catheter capable of deliveringsaid non-particulate agent. In another embodiment, the catheter capableof delivering said polymer or prepolymer composition is different fromthe catheter capable of delivering said non-particulate agent. In thislatter embodiment, the kit further comprising a catheter capable ofdelivering said non-particulate agent.

In another embodiment, the kit further comprises a microballoon catheterto arrest blood flow.

Utility

The methods described herein are useful in embolizing mammalian bloodvessels which, in turn, can be used to prevent/control bleeding due tolesions (e.g., organ bleeding, gastrointestinal bleeding, vascularbleeding, bleeding associated with an aneurysm) or to ablate diseasedtissue (e.g., tumors, etc.). Accordingly, these methods find use inhuman and other mammalian subjects requiring embolization of bloodvessels.

The kit of parts described herein find particulate utility for use withthese methods because the kit conveniently provides all of thecomponents required to practice the described methods.

It is contemplated that the methods described herein can also beemployed non-vascularly, for example, in fallopian tubes or the vasdeferens to effect female and male sterilization respectively.

The following examples are set forth to illustrate the claimed inventionand are not to be construed as a limitation thereof.

EXAMPLES

Unless otherwise stated, all temperatures are in degrees Celsius. Also,in these examples and elsewhere, the following abbreviations have thefollowing meanings:

cc = cubic centimeter DMSO = dimethylsulfoxide EVOH = ethylene vinylalcohol copolymer mm = millimeter μm = micron

In the following examples, Examples 1-2 illustrate the preparation ofpolymer compositions useful in the methods described herein whichpolymer compositions comprise cellulose acetate and EVOH. Examples 3 and4 illustrate how such polymer compositions could be used in the methodsof this invention.

Example 1

A cellulose diacetate polymer composition was prepared by dissolvingcellulose acetate (39.7 weight percent acetyl content) into DMSO toprovide for an 6.8 weight percent concentration of the copolymer inDMSO. To this solution was added either tantalum (10 weight percent,available from Leico Industries, New York, N.Y., U.S.A., 99.95% purity,less than 43 μm in size) or metrizamide (38.5 weight percent, availablefrom Aldrich Chemical Company, Milwaukee, Wis., U.S.A.) as a watersoluble contrast agent.

In the tantalum composition, tantalum settling can result from prolongedstanding. Sonification may help but thorough mixing prior to use isrequired.

Example 2

An EVOH polymer composition was prepared by dissolving EVOH (44 molepercent ethylene) into DMSO to provide for an 6.8 weight percentconcentration of the copolymer in DMSO. In order to facilitatedissolution, the system can be heated to 50° C. overnight.

To this solution was added either tantalum (10 weight percent, availablefrom Leico Industries, New York, N.Y., U.S.A., 99.95% purity, less than43 μm in size) as a water soluble contrast agent or metrizamide (38.5weight percent, available from Aldrich Chemical Company, Milwaukee,Wis., U.S.A.) as a water soluble contrast agent.

In the tantalum composition, tantalum settling can result from prolongedstanding. Sonification may help but thorough mixing prior to use isrequired.

Example 3

The purpose of this example is to illustrate how an in vivo applicationof the methods of this invention in the embolization of a blood vesselcould be accomplished.

In this example, a 50 pound male hound is prepared for blood vesselembolization using an embolic composition comprising 5.8 weight percentEVOH polymer (containing 48 weight percent ethylene), 20 weight percenttantalum in DMSO. This composition is loaded into a syringe andembolization of the left kidney is proceeded by placement of a 3F microcatheter into the kidney through a 5F AngioDynamics Headhunter catheter.The catheter is advanced into the renal artery, flushed with contrastagent to identify the location. Platinum coils are then delivered intothe renal artery via the catheter followed by flushing with DMSO. TheEVOH polymer composition (0.3 cc) is then delivered to this vascularsite. The EVOH composition is quickly injected into the renal artery.After delivery, the DMSO is the EVOH composition rapidly diffuses andthe EVOH precipitates around the platinum coil resulting in embolizationof the upper pole of the kidney.

Example 4

The purpose of this example is to illustrate how an in vivo applicationof the methods of this invention in the treatment of an aneurysm couldbe accomplished.

A 10-15 kg mongrel dog is anesthetized. Under sterile conditions andwith the aid of an operating microscope, an experimental aneurysm issurgically created in the carotid artery using a jugular vein pouch,employing the method of German et al.¹² After about one week, theaneurysm is embolized with a combination of microcoils and liquidembolic composition.

Specifically, the femoral arteries are accessed by cut down andintroducers and 7 Fr guiding catheters are placed. Microcoils areintroduced into the aneurysm by placing a microcatheter (e.g., Tracker®and guide wire) through the guiding catheter and positioning thecatheter tip into the aneurysm under fluoroscopic guidance. One or moreplatinum microcoils are pushed through the microcatheter into theaneurysmal sac, where they are disengaged and deposited. Flushing withcontrast solution confirms microcoil placement. The microcatheter isremoved.

For deposition of the liquid polymer composition, a microcatheter (e.g.,Tracker 18®, with guide wire) is placed through the guiding catheter andis positioned under fluoroscopic guidance so that the catheter tip is inthe aneurysmal sac. A microballoon catheter (4-5 mm balloon) is placedin the carotid artery proximal to the aneurysm. Position is confirmedwith injection of contrast agent. The balloon is inflated to slow orarrest blood flow to prevent displacement of the liquid polymercomposition during injection.

Approximately 0.3 to 0.5 cc of liquid polymer composition is injectedinto the aneurysm over 1 to 2 minutes to fill the aneurysm space. Careis given not to overfill the aneurysm and block the parent artery withpolymer. Filling is easily visualized with fluoroscopy due to thepresence of contrast agent in the polymer composition. After about 5minutes, the polymer is fully precipitated and the catheters are removedfrom the artery.

It is understood that the same procedures set forth above can beemployed with compositions employing liquid prepolymers. However, whenso employed, the timing and injection rates will vary depending on thecure rate for the prepolymer. Such factors are within the skill of theart.

From the foregoing description, various modifications and changes in thecomposition and method will occur to those skilled in the art. All suchmodifications coming within the scope of the appended claims areintended to be included therein.

What is claimed is:
 1. A method for embolizing a vascular site in apatient's blood vessel which method comprises (a) introducing, via acatheter, at the vascular site to be embolized a non-particulate agentor a plurality of said agents; (b) delivering, via a catheter, to saidvascular site a polymer composition comprising a biocompatible polymer,dimethyl sulfoxide and a water insoluble contrast agent wherein saiddelivery is conducted under conditions wherein a polymer precipitateforms in situ at said vascular site thereby embolizing the blood vesseland further wherein said non-particulate agent acts as a structurallattice for precipitate growth.
 2. The method according to claim 1wherein said water insoluble contrast agent is selected from the groupconsisting of tantalum, tantalum oxide, tungsten and barium sulfate. 3.A method for embolizing an aneurysm in a mammalian patient which methodcomprises (a) introducing, via a catheter, into the aneurysm cavity ametallic coil or a plurality of metallic coils; (b) delivering, via acatheter, to said cavity a polymer composition comprising ethylene vinylalcohol copolymer, dimethyl sulfoxide and a water insoluble contrastagent selected from the group consisting of tantalum, tantalum oxide,tungsten and barium sulfate wherein said delivery is conducted underconditions wherein a polymer precipitate forms in situ in the aneurysmcavity thereby blocking the aneurysm and further wherein said metalliccoil acts as a structural lattice for precipitate growth.
 4. The methodaccording to claim 3 wherein said water insoluble contrast agent istantalum.
 5. The method according to claim 3 wherein the polymercomposition is injected into the aneurysm at a rate of about 0.05 to 0.3cc/minute.
 6. The method according to claim 3 wherein the polymercomposition is injected into the aneurysm at a rate of at least 0.6cc/minute.
 7. A method for embolizing a vascular site in a patient'sblood vessel which method comprises (a) introducing, via a catheter, atthe vascular site to be embolized a non-particulate agent or a pluralityof said agents; and (b) delivering, via a catheter, to said vascularsite a prepolymer composition comprising a biocompatible prepolymer anda water insoluble contrast agent wherein said delivery is conductedunder conditions wherein said prepolymer polymerizes in situ in saidvascular site thereby embolizing the blood vessel and further whereinsaid non-particulate agent acts as a structural lattice for solidpolymer formation.
 8. The method according to claim 7 wherein saidprepolymer composition further comprises a biocompatible solvent.
 9. Themethod according to claim 8 wherein said biocompatible solvent isselected from the group consisting of dimethylsulfoxide, ethanol, andacetone.
 10. A method for embolizing a vascular site in a patient'sblood vessel which method comprises (a) introducing, via a catheter, atthe vascular site to be embolized a non-particulate agent or a pluralityof said agents; (b) delivering, via a catheter, to said vascular site apolymer composition comprising a biocompatible polymer, dimethylsulfoxide and a water insoluble contrast agent wherein said delivery isconducted under conditions wherein a polymer precipitate forms in situat said vascular site thereby embolizing the blood vessel and furtherwherein said non-particulate agent becomes fixed against a vascular wallthereby anchoring an embolic site.
 11. The method according to claim 10wherein said water insoluble contrast agent is selected from the groupconsisting of tantalum, tantalum oxide, tungsten and barium sulfate. 12.The method according to claim 10 wherein said non-particulate agent is ametallic coil or a plurality of metallic coils.
 13. The method accordingto claim 12 wherein said metallic coil is a platinum coil.
 14. A methodfor embolizing an aneurysm in a mammalian patient which method comprises(a) introducing, via a catheter, into the aneurysm cavity a metalliccoil or a plurality of metallic coils; (b) delivering, via a catheter,to said cavity a polymer composition comprising a ethylene vinyl alcoholcopolymer, dimethyl sulfoxide and a water insoluble contrast agentselected from the group consisting of tantalum, tantalum oxide, tungstenand barium sulfate wherein said delivery is conducted under conditionswherein a polymer precipitate forms in situ in the aneurysm cavitythereby blocking the aneurysm and further wherein said metallic coilbecomes fixed against a vascular wall thereby anchoring an embolic site.15. The method according to claim 14 wherein said water insolublecontrast agent is tantalum.
 16. The method according to claim 14 whereinthe polymer composition is injected into the aneurysm at a rate of about0.05 to 0.3 cc/minute.
 17. The method according to claim 14 wherein thepolymer composition is injected into the aneurysm at a rate of at least0.6 cc/minute.
 18. A method for embolizing a vascular site in apatient's blood vessel which method comprises (a) introducing, via acatheter, at the vascular site to be embolized a non-particulate agentor a plurality of said agents; and (b) delivering, via a catheter, atthe vascular site a prepolymer composition comprising a biocompatibleprepolymer and a water insoluble contrast agent wherein said delivery isconducted under conditions wherein said prepolymer polymerizes in situat said vascular site thereby embolizing the blood vessel and furtherwherein said non-particulate agent becomes fixed against a vascular wallthereby anchoring an embolic site.
 19. The method according to claim 18wherein said prepolymer composition further comprises a biocompatiblesolvent.
 20. The method according to claim 19 wherein said biocompatiblesolvent is selected from the group consisting of dimethylsulfoxide,ethanol, and acetone.